Interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor (GM-CSF) are endogenous immune activators. Earlier studies using soluble IL-12 and GM-CSF as vaccine adjuvants were unsuccessful due to toxicity or suboptimal response. Metaclipse Therapeutic Corporation has developed versions of IL-12 and GM-CSF with a glycosylated phosphatidylinositol (GPI) anchor added at the carboxyl terminus, allowing incorporation into lipid bilayers such as in influenza virus-like particles (VLPs). Previous studies in young and aged mice using GPI-GM-CSF and GPI-IL-12 incorporated influenza H1 VLPs induced strong humoral and cellular immunity that protected both young and aged mice from homologous and heterologous viral challenge. This SBIR project will assess the long-term protection in preclinical animal models and engage in IND-enabling activities. Currently, elderly patients fail to respond well to influenza vaccines. This SBIR project will contribute to the development of safe and effective adjuvant combinations that can be used to enhance the efficacy of influenza and other antiviral vaccines critically needed for the elderly.